O’Fallon served in the Indian Wars and the War of 1812. He then moved to St. Louis where he and his partners, Alexander McNair and James Kennerly, were suppliers for many army posts in the West. He invested his newly acquired wealth in many enterprises, including the Branch Bank of the United States, in which he was president. He also helped promote the Pacific Railroad, the Ohio and Mississippi, and the North Missouri Railroads.

O’Fallon built medical buildings for Saint Louis University School of Medicine and the Polytechnic Institute of Washington University, as well as a Methodist Church on the corner of Fourth Street and Washington. He also built a mansion on his estate, called Athlone, above the Mississippi River on the north end of St. Louis. The City eventually purchased it and set up a public park, O’Fallon Park, in honor of the family. O´Fallon, Illinois is also named after him.